Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome

项目摘要 这项新的R01申请题为“确定细胞特异性机制，驱动异常骨再生在唐 综合征”的重点是确定机制和细胞的变化，驱动年龄和性别特异性的骨骼缺陷， 再生以及使用唐氏综合征（DS）的多种鼠模型拯救骨再生。所有个人 患有DS的患者表现出标志性骨骼缺陷，即身材矮小和颅面畸形， 低骨矿物质密度（BMD）的性二态性和可变谱，使这一脆弱群体易于 骨骼损伤值得注意的是，男性DS患者比DS患者表现出更早的发病和更大的低BMD倾向 女性最近使用DS小鼠模型（Dp16和Ts65Dn小鼠）的研究平行了变异性和性别差异。 在DS患者中观察到的二态性低BMD，表明雄性DS小鼠的骨折愈合严重受损， Dp16雌性小鼠，而Ts65Dn雌性小鼠以与野生型对照相似的速度愈合骨折。这些发现 证明了DS小鼠的低BMD如何转化为损伤环境，如果在人类中重现， 对这个高危群体的深远影响，特别是随着年龄的增长。为了了解复杂的骨愈合表型， DS，该项目利用哺乳动物模型的骨再生，截肢的趾尖，终末指骨（P3），作为 以及具有内在不同骨累积机制的多种DS小鼠模型（Dp16和Ts65Dn小鼠） 这概括了在DS患者中观察到的性二态性低BMD表型。目标1的研究将建立一个 在急性P3骨损伤反应背景下的扩展和高分辨率DS转录组数据库，以及 在多种DS小鼠模型中表征骨再生过程中破骨细胞和成骨细胞的募集和活性。 目标2中的研究将使性二态性DS相关影响与性二态性年龄相关影响分离 对破骨细胞和成骨细胞的影响。目标3将确定骨合成代谢剂的能力 (PTH和抗sclerostin抗体）来挽救DS小鼠中的骨再生。该项目的成功完成将 为开发微调的性别和年龄特异性治疗提供基础，以减轻骨质疏松的后果 治疗DS患者。

PROJECT SUMMARY This new R01 application entitled “Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome” is focused on identifying the mechanistic and cellular changes that drive age-and-sex-specific deficits in skeletal regeneration as well as rescuing bone regeneration using multiple murine models of Down syndrome (DS). All individuals with DS exhibit hallmark skeletal defects, i.e. short stature and craniofacial abnormalities, and collectively present with a sexually dimorphic and variable spectrum of low bone mineral density (BMD) that predisposes this vulnerable group to skeletal injuries. Remarkably, male DS patients display an earlier onset and greater propensity for low BMD than DS females. Recent studies using murine models of DS (Dp16 and Ts65Dn mice) to parallel both the variability and the sexually dimorphic low BMD observed in DS patients, have shown that fracture healing is severely impaired in male DS mice and female Dp16 mice, whereas Ts65Dn females heal fractures at a similar rate as wild-type controls. These findings demonstrate how low BMD in DS mice translates to an injury environment that if recapitulated in humans would have profound consequences for this at-risk group, especially as they age. To understand the complex bone healing phenotype in DS, this project utilizes a mammalian model of bone regeneration, amputation of the digit tip, the terminal phalanx (P3), as well as multiple DS murine models (Dp16 and Ts65Dn mice) that possess inherently different mechanisms of bone accrual that recapitulate the sexually dimorphic low BMD phenotype observed in DS patients. Studies in Aim 1 will establish an expansive and high resolution DS transcriptome database in the context of an acute P3 bone injury response, as well as characterize osteoclast and osteoblast recruitment and activity during bone regeneration in multiple murine models of DS. Studies in Aim 2 will decouple the sexually dimorphic DS-related impacts from the sexually dimorphic aged-related impacts on osteoclasts and osteoblasts in the setting of bone regeneration. Aim 3 will determine the capacity for bone anabolic agents (PTH and anti-sclerostin antibody) to rescue bone regeneration in DS mice. The successful completion of this project will provide the foundation for developing fine-tuned sex-and-age-specific therapies to mitigate the consequences of poor bone healing in DS individuals.